Carbazole derivatives



United States Patent 3,541,088 CARBAZOLE DERIVATIVES Othmar Schindler, Gurzelen, Switzerland, assignor to Dr.

A. Wander S.A., Bern, Switzerland, a corporation of Switzerland No Drawing. Filed Nov. 13, 1967, Ser. No. 682,637 Claims priority, application Switzerland, Nov. 16, 1966,

16,461/66; June 2, 1967, 7,865/67 Int. Cl. C07d 27/68 US. Cl. 260-440 9 Claims ABSTRACT OF THE DISCLOSURE Carbazole derivatives of the formula:

R2 (:1) wherein R and R are the same or diflerent and denote lower alkyl, aminoalkyl, monoalkylated aminoalkyl or dialkylated aminoalkyl or R and R together with N form pyrrolidinyl (1), piperidino, morpholino, piperazinyl (1), 4-(1ower alkyl)-piperazinyl (1), 4-(lower hydroxyalkyl)-piperazinyl (1), 4-(acylated lower hydroxyalkyl)-piperaziny1 (1); or 4-(alkoxy lower alky1)-piperazinyl (1) having at most 6 carbon atoms in the alkoxyalkyl radical; and (b) the acid addition salts of (a). These compounds exhibit strong anti-convulsant activity, and the free base and the non-toxic acid addition salts are adapted for use as antiepileptic drugs.

This invention is concerned with new carbazole derivatives of the formula:

B2 (II) and acid addition salts thereof. In Formula I R and R are the same or dilfercht and denote lower alkyl, aminoalkyl, monoalkylated aminoalkyl or dialkylated aminoalkyl, or R and R together with N form pyrrolidinyl (1), piperidino, morpholino, piperazinyl (l), 4-(lower alkyl)-piperazinyl -(1), 4- (lower hydroxyalkyl)-piperazinyl (1), 4- (acylated lower hydroxyalkyl)-piperazinyl (1); or 4-(alkoxy lower alkyl)-piperazinyl (1) having at most 6 carbon atoms in the alkoxyalkyl radical. Lower alkyl or 3,541,088 Patented Nov. 17, 1970 hydroxyalkyl is intended to indicate, throughout the specification and claims, an alkyl or hydroxyalkyl group having at most 3 carbon atoms.

The Belgian patent specification No. 539,438 discloses carbazole derivatives of the formula:

in which A denotes a straight or branched saturated hydrocarbon chain having 2 to 6 carbon atoms, and R represents hydrogen, alkyl having at most 6 carbon atoms, aryl or an arylaliphatic radical, and derivatives thereof which are substituted by halogen, alkyl or alkoxy having at most 6 carbon atoms, aryl or aryloxy in the nuclei and/or methylated in the piperazine ring. These compounds show an anticonvulsant action and are disclosed to be suitable for use as antiepileptics; 1-(4-ethyl-piperaziny1-1-) -2-(carbazolyl-9-)-ethane being especially effective.

Surprisingly it has now been found that by replacing the saturated group A by the unsaturated 2-butenylene group the activity is considerably increased and that this enhanced activity is not confined to 1-(piperaziny1-1-)-4- (carbazolyl-9-) -2-butenes but can be generally observed in the 1-amino-4-(carbazolyl-9-J-2-butenes according to Formula I.

The following Table I shows a comparison of activities between carbazole derivatives according to the invention and 1 (4-ethyl-piperazinyl-1-)-2-(carbazolyl-9-)-ethane which is given as the most active of the compounds according to Belgian patent specification No. 539,438. The anticonvulsant action was determined by the electro-shock test [method of Goodman et al., J. pharmacol. 108, 168 (1953)]. ED 50 denotes that dose of known product or of a product according to the invention at which 50% of the test animals are protected against tonic extensor seizure of the hind extremities. Also given in Table I is the oral toxicity on the mouse as LD 50 as well as the oral toxicity on the rat as ED 50 (neurological abnormalities). LD 50 denotes the dose at which 50% of the mice die whereas ED 50 is the dose at which 50% of the rats show first neurological abnormalities (e.g. ataxia).

From Table I it is evident that the new carbazole derivatives according to the invention are superior to the preknown 1 (4-ethyl-piperazinyl-1-)-2-(carbazolyl-9-)- ethane with regard to the anticonvulsant activity as well as with regard to the ratio of toxicity to activity.

TABLE I Toxicity ED 50 Electromg./kg., p.o. I sholclir ED 50 [k LD 50 1neurolpiggical mg. g., p.o. mg, g., p.o. a nonna les Active substance (rat) (mouse) (rat) (a) Known product: 1-(4-ethyl-piperaZinyl-1-)-2- (carbazo1y1-9-) -ethane 332 450 400 (b) Products according to the invention:

l-drethylamino i-(carbazo1yl-9)-cisbutene(2) oxalate 18 480 1piperidino-4-(carbazolyl-Q)-cisbutene(2) 15 360 200 1-(4-111ethy1-piperaziny1-1-)-4-(carbazolyl-9-)-transbutene(2) dioxalate 16 680 800 1-(4-methyl-piperazinyl-1-)-4-(carbazolyl9-)-cis-butene(2) 17 460 200 1-( i-ethyLpipcraZinyl-L)A-(carbazolyl-9-)-transbutene(2) oxalate 17 1-(4-B-hydroxyethyl-piperazinyl-L)-4-(carbaZolyl-9-)- cis-butene(2) dihydrochloride 9 460 325 1-(4-B-ethoxyethyl-piperaziny1-1-)-4-(carbazolyl-9-)- cis-butene(2) hydrochloride 13 250 The new compounds of this invention can be administered in dosage unit form to subjects suffering from any type of epilepsy, these pharmaceutical preparations containing, besides the active substance, organic or inorganic solid or liquid carriers suitable for enteral or parenteral administration. The pharmaceutical preparations may be, for instance, in the form of tablets, dragees, or solutions for injection, one dosage tlnit containing from to 60 mg. of active substance, depending on its nature, on the route of administration and on the physicians prescription, the effective daily dose amounting from to 180 mg. of active substance.

The desired compounds of Formula I are obtained by reducing a compound of the formula:

wherein R and R have the meaning stated above, or an acid addition salt thereof. The reduction is performed, for instance, by treatment with hydrogen in the presence of a catalyst, e.g. Raney iron, Raney nickel or palladium, preferably however, in the presence of a deactivated palladium catalyst; by electrolysis; by treatment with complex hydrides, especially lithium aluminium hydride; or by treatment with metals, such as sodium, potassium or lithium in ammonia. According to the nature of the reducing agent there are usually obtained either cisor trans-substituted products.

The compounds of Formula II used as starting materials are obtained, for example, by reacting 9-(2-propynyl)-carbazole with amines of the formula HNR R in the presence of formaldehyde according to the Mannich reaction.

The desired compounds (I) are also obtained by reacting amines of the formula Z-H, if desired, after prior or during simultaneous action by a condensing agent, with reactive esters of alcohols of the formula Y-CH CH CH-CH OH In these formulae, Z and Y are mutually interchangeable and denote on the one hand the carbazolyl(9) group and on the other hand the basic group As reactive esters of alcohols of the formula Y-CH CH CHCH OH those of hydrohalic acids are especially suitable. The use of a condensing agent is indicated when 9-unsubstituted carbazole is used as starting material. Suitable condensing agents are alkali metals, their hydrides or amides or other alkali metal compounds. Especially suitable is lithium amide.

Hydrohalic acid esters of alcohols of the formula:

which may be used as starting materials are in turn obtainable by reacting carbazole, if desired, after prior or during simultaneous action by a condensing agent of the type mentioned above, with a l,4-dihalogeno-butene(2).

Compounds obtained according to one of these processes in which NR R forms a 4-unsubstituted piperazinyl(1) group may subsequently be alkylated, hydroxyalkylated or alkoxyalkylated in a way known per se.

Furthermore, compounds in which -NR R forms a 4- (hydroxyalkyl)-piperazinyl(1) group may subsequently be acylated.

The compounds of Formula I may be obtained and used either as free bases or in the form of their addition salts with suitable acids, eg hydrohalic acids, toluene-sulphonic acids, sulphuric, nitric, phosphoric, acetic, oxalic, malonic, succinic, malic, maleic, or tartaric acid.

EXAMPLE 1 5.0 g. of 1-morpholino-4-(carbazolyl-9-)-butyne(2) are dissolved in ml. of absolute ethanol, treated with 1.6 g. of a palladium catalyst which has been inactivated with lead salts, and hydrogenated with hydrogen under normal pressure at 20 C. Hydrogenation is stopped when 520 ml. of gaseous hydrogen have been taken up. The reaction mixture is then filtered and concentrated by evaporation in vacuo. The residue is crystallised from ether/ hexane, whereby 2.7 g. of 1-morpholino-4-(carbazolyl- 9)-cis-butene(2) of melting point 67-70 C. are obtained. The oxalate of this base melts at l85-188 C.

The starting material used in this example is obtained as follows:

10.0 g. of 9-(2-propynyl)carbazole (melting point 98- 101 C.) are dissolved in 80 ml. of dioxane, and 2.05 g. of trioxane and 5.1 g. of morpholine are added. After addition of 0.1 g. of copper(l)chloride, the reaction mixture is heated on a steam bath for 1 hour. The reaction mixture is then concentrated by evaporation in vacuo, and the residue is taken up in chloroform/ether and extracted by shaking three times with 2 N hydrochloric acid and once with Water. The aqueous solutions are then extracted once with chloroform/ether. The combined aqueous solutions are then made alkaline with ammonia and extracted by shaking three times with chloroform/ether. The chloroform/ether extracts, washed with water and dried with sodium sulphate, yield after concentration by evaporation 13.0 g. of l-morpholino 4 (earbazolyl-9)-butyne(2), which after crystallisation from ether/hexane forms colourless crystals of melting point -98 C.

EXAMPLE 2 3.4 g. of 1-dimethylamino-4-(carbazolyl-9)-butyne(2) in 180 m1. of absolute tetrahydrofuran are heated together with 2.0 g. of lithium aluminium hydride under reflux with exclusion of moisture for three days. The excess lithium aluminium hydride is then destroyed by adding ethyl acetate. The residue obtained after evaporation of the solution in vacuo is taken up in ether and separated in a usual manner into neutral and basic constituents, whereby 2.7 g. of crude 1-dimethylamino-4- carbazoly1-9)-butene(2) are obtained. The oxalate obtained by reacting this base with oxalic acid has after crystallisation from methanol/ether a melting point of 136137 C.

EXAMPLE 3 5.0 g. of 1-(4-5-hydroxyethyl-piperazinyl-1-)-4-(carba zolyl-9-)-butyne(2) are dissolved in ml. absolute ethanol, treated with 1.5 g. of a palladium catalyst, which has been inactivated with lead salts, and hydrogenated with hydrogen under normal pressure at 20 C. The hydrogenation ceases when 310 ml. of gaseous hydrogen have been taken up. The reaction mixture is then filtered to remove the catalyst and concentrated by evaporation in vacuo. The residue obtained is crystallised from methanol/ether and yields 3.0 g. of 1-(4-B-hydroxyethyl-piperazinyl-1-)-4-(carbazolyl-9-)-cis-butene(2) hydrate which after recrystallisation from methanol/ether has a melting point of 116-119 C. The oxalate of the base melts at 226228 C. and the dihydrochloride at 231-234 C.

EXAMPLE 4 5.9 g. of 1-chloro-4-(carbaZolyl-9-)-trans-butene(2), obtained as mentioned below, in 70 ml. of toluene are heated with 4.0 g. of piperidine at reflux for 22 hours.

After cooling, the reaction mixture is diluted with ether and separated in a usual manner into neutral and basic constituents, whereby 4.3 g. of crude 1 piperidino-4- (carbazoly1-9-)-trans-butene(2) are obtained. The oxalate obtained by reacting this base with oxalic acid shows after crystallisation from methanol/ether the form of colourless platelets of melting point 169-172 C.

The 1-chloro-4- (carbazolyl-9-)-trans-butene(2) used as starting material is obtained in the following way:

5.0 g. of carbazole in 100 ml. of dioxane are heated for 4 hours at reflux under anhydrous conditions with 0.8 g. of lithium amide. After cooling to about 30 C. 12.5 g. of 1,4'dichloro-trans-butene(2) are added and the reaction mixture is heated for another 12 hours at reflux while stirring. The reaction mixture is then concentrated in vacuo and the residue is taken up in chloroform/ether. The chloroform/ether phase is washed with 2 N hydrochloric acid, 2 N sodium carbonate solution and water and then dried over sodium sulphate and evaporated. There are obtained 9.5 g. of an oily neutral crude product from which 2.9 g. of unreacted carbazole are recovered. 20

6 EXAMPLE 5 5.2 g. of 1-piperidino-4-(carbazolyl-9-)-butyne(2) in 200 ml. of absolute tetrahydrofuran are heated together with 2.7 g. of lithium aluminium hydride at reflux with exclusion of moisture for 2 /2 days. The excess lithium aluminium hydride is then destroyed by adding ethyl acetate. The residue obtained after evaporation of the solution in vacuo is taken up in ether and separated in a usual manner into neutral and basic constituents. There are obtained 4.0 g. of crude l piperidino-4-(carbazolyl-9'-)- trans-butene(2) which is converted to the oxalate 'by treating with oxalic acid. After crystallisation from methanol/ ether 4.7 g. of 1-piperidino-4-(carbazolyl-9 )-trans-butene(2) oxalate in the form of colourless crystals of melting point 168-170" C. are obtained, which product is identical to that obtained according to Example 4.

In a like manner as in the examples previously mentioned there are obtained from the corresponding starting materials the products listed in the following Table H, in which R and R have the meaning stated earlier.

TABLE II Example R2 Form Physical constants 6 'N(CH CiS.... Base M.P. 77-78 C.

7 -N(O2H5)2 Cis.- Oxalate M.P. 127-129 C.

8 N CiS ..do M.P. 197200 C;

9 N Cis...- Base M.P. 82-83 C.

10 -N N-CHa CiS "d0 M.P. 109110 C;

11 N N-C H3 Trans. Dioxalate MI, 228-230 C;

12 --N(CHa)CH2CH2N(C2 5)2 C --d0 M P. 128130 O;

13 N /NC2H5 Trans do M P. 233-235 C;

14 N N-C2Hs Cis...- Dihydrochloride M.P. 234240 O;

15 -N N-CHz-CH2-0CHa Cis do M.P. 225-229 C;

16 N N-CH2-CHzOC2Hs Cis --do M.P. 190-194. 0;

17 N N-OH2CH2OC OC(CHs)a Cis. -.d0 M.P. 210-215 C;

1s N /N-CHzCHz-0-C 0-CeHxa Cis---. Dioxalate M.P. 222-225 '0.

19 N /NGHaCH2CH-r0H 01s..-. Dihydroehloride-- M.P. 224-227 C.-

20 N N-CHz-CHz-CHz-O CH: (318.... Base M.P. 74-75 C.

21 -N N-CHr-CH2CH2O C2 5 01s---- Dihydrochloride-. M.P. 221-225 C.-

Production of tablets For the manufacture of tablets, the products of this invention can, for instance, be mixed with lactose and granulated with water, parafiin oil, 0.5% sodium alginate or 5% gelatine solution. The dried granulate is compressed into tablets in the presence of the usual auxiliary agents for tabletting, such as talcum, corn starch, colloidal silicic acid, or magnesium stearate. In this way, there are obtained, e.g. tablets of the following composition:

These 110 mg. tablets, which are provided with a crackline, can be administered orally in a dosage of half a tablet to one tablet two to six times per day in the treatment of subjects suffering from any type of epilepsy.

We claim:

1. A compound selected from the class consisting of (A): carbazole derivatives of the formula:

wherein R and R are members of the class consisting of lower alkyl, aminoalkyl, monoalkylated aminoalkyl and dialkylated aminoalkyl, or R and R together with N form a member of the class consisting of pyrrolidinyl(1), piperidino, morpholino, piperazinyl(l), 4-(lower alkyl)- piperazinyl(l), 4 (lower hydroxyalkyl) piperazinyl(l and 4-(alkoxy lower alkyl)-piperazinyl(l); each of the alkyl and alkoxy moieties in any of the above-mentioned substituents containing from 1 to 3 carbon atoms; and (B): acid addition salts of (A).

2. 1-(4-fi-hydroxyethyl-piperazinyl-l-)-4 (carbazolyl- 9-)-cis-butene(2) and its acid addition salts.

3. 1-(4-[i-hydroxyethyl-piperazinyl-l-)-4 (carbazolyl- 9-)-cis-butene(2) dihydrochloride.

4. 1-diethylan1ino-4-(carbazolyl-9-) cis-butene(2) and its acid addition salts.

5. l-piperidino-4-(carbazolyl-9-)-cis-butene(2) and its acid addition salts.

6. l-(4-methyl-piperazinyl 1 -)-4- (carbazolyl 9 transbutene(2) and its acid addition salts.

7. l-(4-methyl-piperazinyl-l-)-4-(carbazolyl-9 cisbutene(2) and its acid addition salts.

8. l-(4-ethyl-piperazinyl-1-)-4-(carbazolyl-9-) transbutene(2) and its acid addition salts.

9. 1-(4-ethoxyethyl-piperazinyl l 4 (carbazolyl- 9-)-cis-butene(2) and its acid addition salts.

References Cited Chemical Abstracts, vol. 55, cols. 8443 to 8444 (1961) (Abstract of French Patent 1,167,510).

Heller et al., Die Makromolekulare Chemie, vol. 73, pp. 48 to 53 (1964).

JOHN D. RANDOLPH, Primary Examiner US. Cl. X.R. 

